NexCAR19 (Talikabtagene Autoleucel) in Relapsed/Refractory B-Cell Malignancies (NexCAR19)

Korábbi kezelés

• Concurrent malignancy except adequately treated non-melanoma skin cancer, in situ carcinoma (≥3 years disease-free), or completely resected malignancy in CR ≥3 years.
• Short-acting leukemia/lymphoma therapies must be stopped >72h before leukapheresis and infusion.
• Steroids must be discontinued >72h prior (<12 mg/m²/day hydrocortisone equivalent allowed).
• Prior allogeneic HSCT.
• Systemic immunosuppressives not discontinued ≥1 weeks before leukapheresis/infusion.
• Anti-proliferative therapy not stopped ≥1 weeks prior.
• Cytotoxic drugs not stopped ≥1 week prior.
• CNS prophylaxis not stopped >1 week prior.
• Radiation not stopped ≥2 days before leukapheresis and ≥1 week before infusion.
  • Low-Grade Lymphoma - Additional Exclusion (23-24)
• Live vaccine ≤6 weeks before conditioning.
• Acute graft-versus-host disease (GVHD) of Grade II-IV according to the Glucksberg criteria or Grade B-D according to the IBMTR index; or acute or chronic GVHD requiring systemic treatment within 4 weeks prior to enrollment.

Más betegség

• Uncontrolled life-threatening infection (e.g., positive blood culture ≤72h before infusion).
• HIV positive.
• Active HBV replication or active HCV (RNA positive).
• Unstable angina or MI within 6 months.
• Uncontrolled cardiac arrhythmia.
• Hypersensitivity to CAR-T product excipients.
• Active autoimmune/inflammatory neurologic disorders.

Laborértékek

• A minimum interval of ≥4 weeks is required between donor lymphocyte infusion (DLI) and leukapheresis, and ≥4 weeks between DLI and CAR-T cell infusion. This requirement applies to prior antibody-based therapies, including anti-CD20, anti-CD22, anti-CD79a, and similar agents.

Egyéb

• All participants must meet Exclusion Criteria 1-14.
  • Additionally:
• High-grade lymphoma: 15-22
• Low-grade lymphoma: 23-24
• B-ALL: 25
  • General Exclusion Criteria (All Cohorts)
• Pregnant or breastfeeding.
• Primary immunodeficiency.
• Burkitt lymphoma/leukemia.
• Investigator deems subject unable to comply.
  • High-Grade Lymphoma - Additional Exclusion (15-22)
• Active CNS involvement.
• Tumor mass effect requiring urgent treatment.
  • B-ALL - Additional Exclusion (25)

• All participants must meet Inclusion Criteria 1-13.
  • Additionally:
• High-grade lymphoma subjects must meet Criteria 14-18.
• Other B-cell lymphoma subjects must meet Criteria 19-24.
• B-ALL subjects must meet Criteria 25-29.
  • General Inclusion Criteria (Applicable to All Cohorts)
• Age ≥18 years.
• Patients approved for leukapheresis by the CAR-T cell treatment council.
• ECOG performance status <2.
• Life expectancy ≥12 weeks.
• Renal Function: Estimated creatinine clearance ≥60 mL/min (Cockcroft-Gault) → fludarabine/cyclophosphamide lymphodepletion.
  • In lymphoma cohort patients with creatinine clearance 30-60 mL/min, bendamustine may be used as an alternative due to cumulative fludarabine toxicity and neurotoxicity risk.
• Liver Function:
  • ALT and AST ≤3 × ULN unless attributable to underlying malignancy.
  • Total bilirubin ≤2 × ULN except in Gilbert syndrome, isolated unconjugated hyperbilirubinemia, or if attributable to underlying malignancy.
• Hemodynamically stable with LVEF ≥45% (confirmed by echocardiography or MUGA scan).
• Baseline oxygen saturation >92% on room air.
• ANC ≥500/µL (may be waived if cytopenia due to underlying malignancy at investigator discretion).
• Platelet count ≥50,000/µL (may be waived if cytopenia due to underlying malignancy at investigator discretion).
• Negative serum or urine pregnancy test (within 24 hours prior to conditioning therapy) in women of childbearing potential; also negative prior to leukapheresis.
• Sexually active patients (women of childbearing potential and all men) must use highly effective contraception for ≥12 months after CAR-T infusion.
• Written informed consent provided.
  • High-Grade Lymphoma - Additional Inclusion Criteria (14-18)
• Histologically confirmed previously treated:
  • Diffuse large B-cell lymphoma (DLBCL)
  • Primary mediastinal B-cell lymphoma
  • Transformed indolent B-cell lymphoma
  • Follicular lymphoma Grade 3B
  • High-grade B-cell lymphoma
• Chemotherapy-refractory disease defined as:
  • Primary refractory disease
  • Best response to last chemotherapy = PD or SD (biopsy confirmed)
  • Progression/relapse ≤12 months after autologous SCT
  • Relapse ≤12 months after first-line CR (biopsy confirmed)
  • Relapse beyond 12 months if auto-SCT not feasible
• Not eligible for or unwilling to undergo autologous SCT.
• Must have received anti-CD20 monoclonal antibody and anthracycline-containing regimen. Transformed lymphoma subjects must have received ≥2 prior systemic lines.
• Measurable disease per International Working Group (IWG) criteria.
  • Other B-Cell Lymphomas - Additional Inclusion Criteria (19-24)
• Histologically confirmed:
  • Mantle Cell Lymphoma (Cyclin D1 overexpression or t(11;14))
  • Follicular Lymphoma Grade I-IIIA
  • Marginal Zone Lymphoma
• Relapsed or refractory disease:
  • MCL: ≤5 prior regimens including:
  • Anthracycline or bendamustine
  • Anti-CD20 antibody
  • BTK inhibitor (ibrutinib or acalabrutinib; intolerance allowed)
  • FL/MZL: Progression after ≥2 combination chemoimmunotherapy regimens (single-agent CD20 or splenectomy not counted).
• Radiologically measurable disease at screening
  • per revised IWG (Cheson 2007): ≥1 measurable lesion
  • Previously irradiated lesions measurable only if progression documented
  • If only nodal disease: ≥1 node ≥2 cm
• No known active CNS lymphoma involvement.
• Prior therapy toxicities resolved to ≤Grade 1 (except alopecia).
• Prior autologous HCT, POD24 status, and prior PI3K inhibitor therapy allowed.
  • B-Cell Acute Lymphoblastic Leukemia (B-ALL) - Additional Inclusion Criteria (25-29)
• Relapsed/Refractory B-ALL meeting one of:
  • Primary refractory disease
  • First relapse ≤12 months
  • ≥2 prior systemic lines
  • Post-allogeneic SCT relapse (≥100 days post-transplant; off immunosuppression ≥4 weeks)
  • Ph+ disease:
  • TKI intolerance
  • Relapsed/refractory after ≥2 TKIs
  • No alternative TKI option
  • Ineligible for allogeneic SCT due to
  • comorbidity,
  • conditioning contraindication,
  • no donor,
  • prior SCT,
  • or refusal (documented).
• Morphological bone marrow disease.
• CD19 tumor expression documented within 3 months (BM or PB by flow cytometry).
• Absolute lymphocyte count ≥100/µL.
• ≥3 half-lives elapsed since prior immune checkpoint inhibitor or stimulatory therapy